Digitalis, digoxin, ouabain and related substances are cardiac glycosides derived from plants. The main pharmacodynamic property of cardiac glycosides is the ability to increase the force of myocardial contraction in a dose-dependent manner (positive inotropic effect). The most probable explanation for the direct positive inotropic effect is the ability of cardiac glycosides to inhibit membrane-bound Na.sup.+, K.sup.+ -activated adenosine triphosphatase (Na.sup.+, K.sup.+ -ATPase) (Hoffman, B. F. and J. T. Bigger, Jr., "Digitalis and Allied Cardiac Glycosides" in The Pharmacological Basis of Therapeutics, eds. Goodman and Gilman, p. 732, (1980)). The hydrolysis of adenosine triphosphate (ATP) by this enzyme provides the energy for the sodium potassium pump.
Relatively little is known about the endogenous regulation of Na.sup.+, K.sup.+ -ATPase. Catecholamines (Phillis, J. W., Cell, Tissue and Organ Cultures in Neurobiology, pp. 93-97 (1978); Horwitz, B. A., Fed. Proc., 38:2170-2176 (1979)), thyroid hormone (Smith, T. J. and I. S. Edelman, Fed. Proc., 38:2150-2153 (1979)), aldosterone (Rossier, B. C., et al., Science, 12:483-487 (1987)), linoleic and linolenic acids (Bidard, J. N., et al., Biochem. Biophys. Acta., 769:245 (1984); Tamura, M., et al., J. Biol. Chem., 260:9672 (1985); and vanadium (Cantley, L. C., Jr., et al., J. Biol. Chem., 243:7361-7368 (1978)) have all been linked to either direct or indirect effects on enzyme activity.
Many researchers have tried to isolate a specific endogenous inhibitor of plasma membrane Na.sup.+, K.sup.+ -ATPase similar to digitalis or ouabain, but of mammalian origin, by measuring immunoreactivity in plasma, to the digoxin radioimmunoassay in situations where the inhibitor might be elevated. Klingsmueller et al. found digitalis like immunoreactivity in the urine of Na.sup.+ -loaded normal human subjects (Klingsmueller, et al., Klin. Wochenschr., 60: 1249-1253 (1982)). Graves, S. W., et al. made a similar observation in the plasma of uremic subjects (Graves, S. W., et al., Ann. Intern. Med., 99:604-608 (1983)).
The definitive structure of plasma, urinary or tissue inhibitor of Na.sup.+, K.sup.+ -ATPase is not known (Haupert, G. T., Jr., in The Na.sup.+ K.sup.+ -Pump, Part B: Cellular Aspects; Skou, J. C., et al., Eds., p. 297-320 (1988)). Furthermore, the degree to which various candidate compounds are truly "digitalis-like" in either structure or function remains controversial, since even those substances characterized in the greatest biochemical detail manifest some differences with the cardiac glycosides, digitalis and ouabain (Carilli, C. T., et al., J. Biol. Chem., 260: 1027-1031 (1985); Crabos, M., et al., Eur. J. Biochem., 162:129 (1987); Tamura, M., et al., Biochem., 27:4244-4253 (1988)).
For example, the digitalis-like factor (DLF) isolated by Graves cross-reacts with antidigoxin antibodies (Graves, S. W., U.S. Pat. No. 4,780,314)). However, DLF has never been shown to be a physiologic inhibitor, as would be expected of an endogenous regulator. By physiologic is meant an inhibitor that has a very high binding affinity for the enzyme; reversibly binds and inhibits; has high specificity for the membrane Na.sup.+, K.sup.+ -ATPase; and is responsive to relevant stimuli.
Because of their positive inotropic effect, cardiac glycosides (e.g., digitalis and ouabain) are unrivaled in value for the treatment of heart failure. Cardiac glycosides are most frequently used therapeutically to increase the adequacy of the circulation in patients with congestive heart failure and to slow the ventricular rate in the presence of atrial fibrillation and flutter.
However, cardiac glycosides have narrow therapeutic indices and their use is frequently accompanied by toxic effects that can be severe or lethal. The most important toxic effects, in terms of risk to the patient, are those that involve the heart (e.g., abnormalities of cardiac rhythm and disturbances of atrio-ventricular conduction). Gastrointestinal disorders, neurological effects, anorexia, blurred vision, nausea and vomiting are other common cardiac glycoside-induced reactions.